US4816444AExpiredUtility
Cell growth inhibitory substance
Est. expiryJul 10, 2007(expired)· nominal 20-yr term from priority
A61P 35/00A61K 38/00C07K 5/0205
98
PatentIndex Score
297
Cited by
2
References
18
Claims
Abstract
A potent cell growth inhibitory substance obtained from the Indian Ocean sea hare Dolabella, herein denominated "dolastatin 10"; and pharmaceutical preparations containing same; and methods useful for the treatment of a host afflicted with neoplastic disease therewith.
Claims
exact text as granted — not AI-modifiedAccordingly, what is claimed is:
1. A cell growth inhibitory substance denominated dolastatin 10 and having the structural formula: ##STR5##
2. A pharmaceutical preparation comprising a pharmaceutically acceptable carrier and an effective amount of a natural or synthetic cell growth inhibitory substance or a non-toxic pharmaceutical active derivative thereof, said substance having the structural formula: ##STR6##
3. A cell growth inhibitory substance according to claim 1 having the following N.M.R. characteristics: ______________________________________
Chemical Shift, ppm
Structure .sup.1 H(mult; J,Hz;
Assignment
13C(mult) Integration) NOE
______________________________________
2 170.51(s) 7.717(d; 3.3; 1H)
4 142.77(d) 7.254(d; 3.3; 1H)
5 118.76(d) 5.516(ddd; 5.7,7.2, 9.3; 1H)
6 53.02(d) 3.399(dd; 5.7,14; 1H)
6a 41.48(t) 3.256(dd; 5.7; 14; 1H)
6b1 137.74(s) 7.243(d; 7.9; 2H)
6b2,6b6
128.74(d)×2
7.214(dd; 7.9,9.2; 2H)
6b3,6b5
129.80(d)×2
7.194(t; 9.2; 1H)
6b4 127.02(d) 7.256(t; 7.6; 1H)
7 9,9a,10,
10ab,11
8 175.67(s) 2.282(quintet; 7.2; 1H)
7
9 44.79(d) 1.085(d; 7.1; 3H)
9a 14.49(q) 3.845(dd; 2.0,8.2; 1H)
7
10 82.05(d) 3.309(s; 3H) 6,7
10ab 60.89(q) 3.985(m; 1H)
11 59.86(d) 1.804(ddd; 5.5,7.0; 19; 1H)
12 25.00(t) 1.608(ddd; 7; 9.2,19; 1H)
1.446(ddd; 4.7,7,19; 1H)
13 25.45(t) 1.715(ddd; 4.7,7.8,12.7; 1H)
3.401(dd; 7.8,10; 1H)
17
14 48.03(t) 3.390(m; 1H).sup.b
16 174.01(s)
17 38.11(t) 2.394(ABq; 9.0; 2H)
14
18 78.86(d) 4.122(broad t; 8.7; 1H)
18ab 58.16(q) 3.313(s; 3H) 22
19 54.11(d) 3.26-3.39(1H).sup.c
19a 33.62(d) 1.680(1H).sup.b
19b 26.25(t) 1.370(broad m; 1H)
1.000(broad m; 1H).sup.b
19c 10.92(q) 0.823(t; 7.4; 3H)
19d 19.82(q) 1.003(d; 6.8; 3H)
20a 30.09(q) 3.012(s; 3H) 22
21 171.39(s)
22 54.20(d) 4.761(dd; 6.5, 8.8; 1H)
18,18ab,
20,19
22a 31.42(d) 1.983(sextet; 6.7; 1H)
22b 18.18(q) 0.941(d; 6.8; 3H)
22c 16.09(q) 0.977(d; 6.8; 3H)
23 6.861(d; 8.9; 1H)
25bc
24 172.44(s)
25 76.77(d) 2.454(d; 6.9; 1H)
23
25bc 49.92(q)×2
2.262(s; 6H) 23
26 28.08(d) 2.073(sextet; 6.7; 1H)
27 20.24(q) 0.964(d; 6.8; 3H)
28 18.18(q) 0.902(d; 6.8; 3H)
______________________________________
.sup.a Residual CHDCl.sub.2 as internal reference (5.32 ppm).
.sup.b Overlapping signal.
.sup.c Signal assigned from NOE data.
4. A pharmaceutical preparation according to claim 2 in which said substance has the following N.M.R. characteristics: ______________________________________
Chemical Shift, ppm
Structure .sup.1 H(mult; J,Hz;
Assignment
13C(mult) Integration) NOE
______________________________________
2 170.51(s) 7.717(d; 3.3; 1H)
4 142.77(d) 7.254(d; 3.3; 1H)
5 118.76(d) 5.516(ddd; 5.7,7.2, 9.3; 1H)
6 53.02(d) 3.399(dd; 5.7,14; 1H)
6a 41.48(t) 3.256(dd; 5.7; 14; 1H)
6b1 137.74(s) 7.243(d; 7.9; 2H)
6b2,6b6
128.74(d)×2
7.214(dd; 7.9,9.2; 2H)
6b3,6b5
129.80(d)×2
7.194(t; 9.2; 1H)
6b4 127.02(d) 7.256(t; 7.6; 1H)
7 9,9a,10,
10ab,11
8 175.67(s) 2.282(quintet; 7.2; 1H)
7
9 44.79(d) 1.085(d; 7.1; 3H)
9a 14.49(q) 3.845(dd; 2.0,8.2; 1H)
7
10 82.05(d) 3.309(s; 3H) 6,7
10ab 60.89(q) 3.985(m; 1H)
11 59.86(d) 1.804(ddd; 5.5,7.0; 19; 1H)
12 25.00(t) 1.608(ddd; 7; 9.2,19; 1H)
1.446(ddd; 4.7,7,19; 1H)
13 25.45(t) 1.715(ddd; 4.7,7.8,12.7; 1H)
3.401(dd; 7.8,10; 1H)
17
14 48.03(t) 3.390(m; 1H).sup.b
16 174.01(s)
17 38.11(t) 2.394(ABq; 9.0; 2H)
14
18 78.86(d) 4.122(broad t; 8.7; 1H)
18ab 58.16(q) 3.313(s; 3H) 22
19 54.11(d) 3.26-3.39(1H).sup.c
19a 33.62(d) 1.680(1H).sup.b
19b 26.25(t) 1.370(broad m; 1H)
1.000(broad m; 1H).sup.b
19c 10.92(q) 0.823(t; 7.4; 3H)
19d 19.82(q) 1.003(d; 6.8; 3H)
20a 30.09(q) 3.012(s; 3H) 22
21 171.39(s)
22 54.20(d) 4.761(dd; 6.5, 8.8; 1H)
18,18ab,
20,19
22a 31.42(d) 1.983(sextet; 6.7; 1H)
22b 18.18(q) 0.941(d; 6.8; 3H)
22c 16.09(q) 0.977(d; 6.8; 3H)
23 6.861(d; 8.9; 1H)
25bc
24 172.44(s)
25 76.77(d) 2.454(d; 6.9; 1H)
23
25bc 49.92(q)×2
2.262(s; 6H) 23
26 28.08(d) 2.073(sextet; 6.7; 1H)
27 20.24(q) 0.964(d; 6.8; 3H)
28 18.18(q) 0.902(d; 6.8; 3H)
______________________________________
.sup.a Residual CHDCl.sub.2 as internal reference (5.32 ppm).
.sup.b Overlapping signal.
.sup.c Signal assigned from NOE data.
5. A method of treating a host afflicted with neoplastic disease comprising administering to said host an effective amount of a natural or synthetic cell growth inhibitory substance or a pharmaceutically active non-toxic derivative thereof, said substance having the structural formula: ##STR7##
6. A method according to claim 5 in which said substance is administered intravenously, at a dosage level of from 0.1 up to about 20 mg per kilogram of host body weight.
7. A method according to claim 5 in which said substance is administered subcutaneously, at a dosage level of from 1 up to about 50 mg per kilogram of host body weight.
8. A method according to claim 5 in which said substance is administered orally, at a dosage level of from 5 up to about 100 mg per kilogram of host body weight.
9. A method according to claim 5 in which said neoplastic disease is lymphocytic leukemia P388.
10. A method according to claim 9 in which said small but effective amount comprises from about 1 up to about 4 μg per kilogram of host body weight.
11. A method according to claim 5 in which said substance has the following N.M.R. characteristics: ______________________________________
Chemical Shift, ppm
Structure .sup.1 H(mult; J,Hz;
Assignment
13C(mult) Integration) NOE
______________________________________
2 170.51(s) 7.717(d; 3.3; 1H)
4 142.77(d) 7.254(d; 3.3; 1H)
5 118.76(d) 5.516(ddd; 5.7,7.2, 9.3; 1H)
6 53.02(d) 3.399(dd; 5.7,14; 1H)
6a 41.48(t) 3.256(dd; 5.7; 14; 1H)
6b1 137.74(s) 7.243(d; 7.9; 2H)
6b2,6b6
128.74(d)×2
7.214(dd; 7.9,9.2; 2H)
6b3,6b5
129.80(d)×2
7.194(t; 9.2; 1H)
6b4 127.02(d) 7.256(t; 7.6; 1H)
7 9,9a,10,
10ab,11
8 175.67(s) 2.282(quintet; 7.2; 1H)
7
9 44.79(d) 1.085(d; 7.1; 3H)
9a 14.49(q) 3.845(dd; 2.0,8.2; 1H)
7
10 82.05(d) 3.309(s; 3H) 6,7
10ab 60.89(q) 3.985(m; 1H)
11 59.86(d) 1.804(ddd; 5.5,7.0; 19; 1H)
12 25.00(t) 1.608(ddd; 7; 9.2,19; 1H)
1.446(ddd; 4.7,7,19; 1H)
13 25.45(t) 1.715(ddd; 4.7,7.8,12.7; 1H)
3.401(dd; 7.8,10; 1H)
17
14 48.03(t) 3.390(m; 1H).sup.b
16 174.01(s)
17 38.11(t) 2.394(ABq; 9.0; 2H)
14
18 78.86(d) 4.122(broad t; 8.7; 1H)
18ab 58.16(q) 3.313(s; 3H) 22
19 54.11(d) 3.26-3.39(1H).sup.c
19a 33.62(d) 1.680(1H).sup.b
19b 26.25(t) 1.370(broad m; 1H)
1.000(broad m; 1H).sup.b
19c 10.92(q) 0.823(t; 7.4; 3H)
19d 19.82(q) 1.003(d; 6.8; 3H)
20a 30.09(q) 3.012(s; 3H) 22
21 171.39(s)
22 54.20(d) 4.761(dd; 6.5, 8.8; 1H)
18,18ab,
20,19
22a 31.42(d) 1.983(sextet; 6.7; 1H)
22b 18.18(q) 0.941(d; 6.8; 3H)
22c 16.09(q) 0.977(d; 6.8; 3H)
23 6.861(d; 8.9; 1H)
25bc
24 172.44(s)
25 76.77(d) 2.454(d; 6.9; 1H)
23
25bc 49.92(q)×2
2.262(s; 6H) 23
26 28.08(d) 2.073(sextet; 6.7; 1H)
27 20.24(q) 0.964(d; 6.8; 3H)
28 18.18(q) 0.902(d; 6.8; 3H)
______________________________________
.sup.a Residual CHDCl.sub.2 as internal reference (5.32 ppm).
.sup.b Overlapping signal.
.sup.c Signal assigned from NOE data.
12. A method according to claim 5 in which said neoplastic disease is murine melanoma.
13. A method according to claim 12 in which said small but effective amount comprises from about 1.44 up to about 11.1 μg per kilogram of host body weight.
14. A method according to claim 5 in which said neoplastic disease is human melanoma.
15. A method according to claim 14 in which said small but effective amount comprises from about 3.25 up to about 26 μg per kilogram of host body weight.
16. A method according to claim 11 in which said substance is administered intravenously, at a dosage level of from 0.1 up to about 20 mg per kilogram of host body weight.
17. A method according to claim 11 in which said substance is administered subcutaneously, at a dosage level of from 1 up to about 50 mg per kilogram of host body weight.
18. A method according to claim 11 in which said substance is administered orally, at a dosage level of from 5 up to about 100 mg per kilogram of host body weight.Cited by (0)
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